Dosage forms for administering combinations of drugs

ABSTRACT

The present invention is directed to dosage forms that can be used in therapeutic methods involving the oral co-administration of a combination of at least two drugs, one of which impairs gastrointestinal absorption and one of which does not. The dosage forms are designed so that the drug impairing absorption is not released into the gastrointestinal tract of a patient until after the drugs that do not impair absorption have been released and substantially absorbed. The invention may be used in treatment of migraine using a combination of triptans and NSAIDs or in the treatment of pain using a combination of NSAIDs and opioid analgesics.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 11/987,970, filed on Dec. 6, 2007, now U.S. Pat. No. 9,265,732,which is a continuation-in-part of U.S. patent application Ser. No.11/712,969, filed on Mar. 2, 2007, which claims priority to, and thebenefit of, U.S. Provisional Application Ser. No. 60/779,393 filed onMar. 6, 2006. The contents of these previous applications are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention is directed to dosage forms for orallyco-administering drugs in cases in which at least one drug, as anunintended consequence of its use, impairs absorption from thegastrointestinal tract of patients, and at least one other drug thatdoes not. The dosage forms delay the release of the absorption-impairingdrug until after the non-absorption impairing drug has been at leastpartially absorbed. Thus, the speed and efficiency of overall deliveryis enhanced. The dosage forms will be of particular value forpharmaceutical compositions in which certain non-narcotic analgesics arecombined with triptans or opioid analgesics.

BACKGROUND OF THE INVENTION

Therapeutic methods involving the co-administration of drugs may be usedin cases where larger doses of a single agent would not have atherapeutic benefit or would result in unacceptable toxicity or sideeffects, or where multiple mechanisms of action may be beneficial. Thisapproach is commonly used in the treatment of pain, viral or bacterialinfection, asthma, hypertension and cancer. For example, opioidanalgesics may be combined with other analgesics such as acetaminophenor non-steroidal anti-inflammatory drugs (NSAIDs, see generally, U.S.Pat. No. 6,451,806). Similarly, in the field of migraine therapeutics,it has been reported that the co-administration of triptans togetherwith NSAIDs results in better overall relief than the administration ofeither agent alone (U.S. Pat. No. 6,586,458).

Unfortunately, there are instances in which one drug in a combination,due to an unwanted pharmacological effect on the gastrointestinal tract,impairs the absorption of other drugs from a patient's gastrointestinaltract. This appears to be true both for drug combinations involving theuse of opioids (Crighton, et al., Anesth. Analg. 87:445-449 (1998)), andfor those involving the use of triptans (Seaber, et al., Eur. J. Clin.Pharm. 53:229-234 (1997)). Impaired absorption of one component in suchcombinations can lead to a delayed onset of action for this componentand to a less than optimal overall therapeutic effect.

A number of approaches have been taken in an attempt to compensate forpoor absorption of drugs from the gastrointestinal tract of patients.These have included the co-administration of an agent that enhancesabsorption (U.S. Pat. No. 5,968,972) or that increases gastric motility(U.S. Pat. No. 6,479,551). Alternatively, drugs can be administered by aroute that avoids a patient's gastrointestinal tract, e.g., usingtransmucosal or transdermal delivery (U.S. Pat. Nos. 5,624,677;6,143,278). While these methods may be useful for certain therapies,alternative approaches would be desirable.

SUMMARY OF THE INVENTION

The present invention is directed to dosage forms for pharmaceuticalcompositions containing at least two drugs; one that impairs absorptionfrom a patient's gastrointestinal tract as an unintended consequence ofits therapeutic use, and one that does not. By designing dosage forms sothat the release of the absorption-impairing drug is delayed until afterthe non-impairing drug has been at least partially absorbed, a morerapid and/or an improved overall therapeutic effect can be achieved. Theinvention should be of value in the treatment of migraine headache usinga combination of an absorption-impairing triptan and a non-absorptionimpairing NSAID. It should also be of value for combinations involvingopioid analgesics and other drugs such as non-narcotic analgesics.

In its first aspect, the invention is directed to a pharmaceuticalcomposition in unit dosage form for oral administration to a patient.The composition contains at least two different drugs: a first drug thatprovides a therapeutic benefit but unintentionally impairs othertherapeutic agents from being absorbed from a patient's gastrointestinaltract, and a second drug that provides a therapeutic benefit but doesnot impair absorption of other therapeutic agents. Both of these drugsshould be present in a therapeutically effective amount, i.e., uponingestion of one or more unit dosage forms by a patient, sufficient drugshould be present to achieve the desired therapeutic effect.

For example, a therapeutically effective amount of an analgesic drug oran NSAID analgesic drug would be a dosage sufficient to reduce pain, orthe swelling and pain associated with inflammation. Similarly, atherapeutically effective dose of a drug administered to treat migraine,would be an amount sufficient to reduce the pain or other symptomsassociated with a migraine attack. Also, it will be understood that, forthe purposes of the present invention, any pharmaceutically acceptableform of a drug may be used including, but not limited to,hydrochlorides, hydrobromides; benzoates; mesylates; phosphates;succinates; and malates. Unless otherwise indicated, reference madeherein to a drug such as a triptan, NSAID, analgesic, opioid analgesicetc., will be understood to encompass all of these and similarpharmaceutically acceptable forms of the drugs, especially allpharmaceutically acceptable salts.

The main characteristic of the dosage form of the present invention isthat it is designed to deliver the drugs in the pharmaceuticalcomposition in a specific coordinated manner. In particular, uponingestion by a patient, the second drug, i.e., the drug that does notimpair gastrointestinal absorption, is released from the unit dosageform before the first, absorption impairing drug. The timing of deliveryis also very important. In general, essentially none of the first drugshould be released from the unit dosage form into the gastrointestinaltract of a patient for a period that is equal to or greater thanone-fourth Tmax2, where Tmax2 is the time interval necessary to reach apeak plasma concentration of the second, non-absorption impairing, drugwhen it is administered to a patient in essentially the same dosage formbut as the sole active agent. In other words, Tmax2 is the time intervalfrom the ingestion of a tablet containing the second drug alone, untilthe plasma level of the drug in a patient reaches a maximum. This is acommon pharmacokinetic parameter that can be determined usingmethodology well known in the art and whose values for different drugsare provided in standard reference works such as the Physician's DeskReference (Medical Economics, Montvale N.J.).

Tmax values typically vary somewhat between people and, as a result,they are sometimes expressed as a range based upon effects observed inmany individuals. For the purposes of the present invention, unlessotherwise indicated, Tmax will be considered to be the middle of anysuch range. For example, if Tmax is recognized in the art as being 1-2hours, for the purposes of the present invention it would be consideredto be 90 minutes and ¼ Tmax would be about 22 minutes. Thus, the phrase“period that is equal to or greater than one-fourth Tmax2” would mean 22minutes or longer. For dosage forms in which, an NSAID or othernon-narcotic analgesic is present as the non-absorption impairingcomponent, the release of the absorption impairing drug should bedelayed for a minimum of 10 minutes, and more preferably the delayshould be for a minimum of 20, 30 or 60 minutes. Unless otherwiseindicated by context, the term “is released” means the time when asubstantial portion of a drug (e.g., greater than 1%) is discharged froma dosage form and enters into the gastrointestinal tract of a patient.

In a preferred embodiment, the pharmaceutical composition describedabove is in the form of a multilayer tablet, preferably whereessentially all of the first, absorption-impairing, drug is surroundedby a membrane that does not release it, or which is formulated withcomponents that delay its release, for a time period at least equivalentto one-fourth Tmax2 and, preferably, for a period of at least one-halfTmax2. The term “essentially all” as used herein refers to greater than90% of the total amount of the drug in a unit dosage form, preferablymore than 95%, and still more preferably to more than 99%. The term“essentially none” refers to less than 10% of the total amount of drugin a dosage form, preferably less than 5% and more preferably less than1%.

In one preferred embodiment, essentially all of the first drug is foundin a single core layer of a tablet surrounded by a membrane describedabove and essentially all of the second drug is located in one or morelayers outside of this core. Alternatively, an agent that delays drugrelease, may be mixed in with the absorption impairing drug. The releasedelaying agent should typically be present in compositions in a range ofbetween 10% and 70% by weight and will constitute either a polymericsubstance which swells and/or a gel. Examples of appropriate agents are:hydroxypropylmethylcellulose; crosslinked polyvinylpyrrolidone;crosslinked sodium carboxymethylcellulose; carboxyvinyl polymers;polyvinyl alcohols and derivatives thereof including derivatives ofethylcellulose, methylcellulose and cellulose. Of these, the mostpreferred is hydroxypropylmethylcellulose.

In an alternative embodiment, the dosage form may be a capsule,preferably in which essentially all of the first drug is located in oneor more particles surrounded by a membrane that does not release thisdrug or is formulated with components that delays release for a periodof at least ½ Tmax2 and preferably for a period of at least Tmax2.Generally, the capsules will contain multiple particles of themembrane-surrounded first drug with essentially all of the second drugbeing located outside of these particles.

Among the preferred absorption-impairing drugs for use in the dosageforms are the triptans, e.g., sumatriptan, eletriptan, rizatriptan,frovatriptan, almotriptan, zolmitriptan and naratriptan. The mostpreferred of these is sumatriptan present in dosage forms in an amountof between 25 and 100 mg, together with a non-narcotic analgesic, suchas acetaminophen or an NSAID, such as naproxen or naproxen sodium at200-600 mg. When naproxen is used, membranes should be designed so thatessentially no triptan is released for a period of at least 45 minutesafter the dosage form is ingested by a patient. In the case of naproxensodium, no triptan should be released for a period of at least 20minutes. If desired, these same parameters may be used for othercombinations of NSAIDs and triptans or for combinations involving opioidanalgesics and non-narcotic analgesics. Dosage forms containing triptansand analgesics may be used to treat patients for migraine headache.

There is a second important consideration attached to the use ofnaproxen sodium in drug combinations. Although this drug does notdirectly impair absorption of other drugs, it is believed that, due toits relatively poor dissolution characteristics in stomach acid, it hasthe potential for entrapping other, faster dissolving, drugs (see e.g.,published US application 2004-0180089) and to thereby impair theirrelease. This is something that one of skill in the art may want to takeinto account when making a dosage form for a particular clinicalobjective. For example, if one wanted the triptan to be releasedquickly, then keeping it separate from the naproxen sodium (e.g., in atablet where triptan and NSAID are in a side by side arrangement) wouldbe desirable. If, instead, the objective is to delay the release oftriptan until a substantial portion of the naproxen can be absorbed,then putting the triptan in a core surrounded by naproxen would be anacceptable arrangement.

Another group of preferred absorption-impairing drugs for use in thedosage forms are the opioid analgesics, e.g., alfentanil, buprenorphine,butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone,hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine,oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentaniland tramadol. Opioid analgesics may be combined with analgesics that donot impair gastrointestinal absorption and administered to patients in atherapeutically effective amount for the treatment of pain.

It will be understood that the dosage forms described above can also beused for compositions having more than one absorption impairing drugand/or more than one non-absorption impairing drug. In these cases,essentially all of the absorption impairing drugs should be containedwithin one or more membranes that delay their release until after all ofthe non-absorption impairing drugs have been released. The Tmax used indetermining the time of release, i.e., Tmax2 should be that of thenon-impairing drug that takes the longest to reach a peak plasmaconcentration, i.e., the one with the longest Tmax.

In all of the dosage forms described above, disintegrants may be used tofacilitate the break up of tablet components after ingestion by apatient. Suitable disintegrants will be known to the person skilled inthe art and a non-limiting list of examples includes croscarmellosesodium, crospovidone, sodium starch glycolate, povidone, crosslinkedpolyvinylpyrrolidone, starch, low substituted hydroxymethylcellulose,methylcellulose, microcrystalline cellulose. Effervescence which resultsfrom a reaction of sodium bicarbonate with an acid when added to watercan also be an effective way to cause disintegration of a tablet. Theacid for this reaction can be provided by the stomach acid, the drugsubstance, the addition of a salt such as tartaric or citric acid or byother acid containing excipients.

Disintegrants may be included with either the absorption-impairing drug,the non-impairing drug or both. They will be of particular value whenadded to the non-impairing drug for the purpose of increasing the amountof drug absorbed by a patient prior to the release of theabsorption-impairing drug. For example, in a tablet where thenon-impairing drug is released immediately and the absorption-impairingdrug is released after 20 minutes, more non-impairing drug should beabsorbed in the presence of a disintegrant than in its absence.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: The figure shows a tablet configuration in which there is a corecontaining a drug that impairs absorption surrounded by an outer layercontaining a drug that does not impair absorption. A: Drug in Core(inner layer); B: Drug in Outer layer

FIG. 2: FIG. 2 shows a bilayer tablet configuration in which anabsorption-impairing drug is in one layer and a drug that does notimpair absorption is in the other layer. C: Drug in Layer 1; D: Drug inLayer 2.

FIG. 3: The figure shows a tablet arrangement in which there is a corethat contains an absorption-impairing drug and this core is surroundedby a film coating containing a drug that does not impair absorption. E:Drug in Core; F: Drug in Film Coat.

FIG. 4: FIG. 4 shows a tablet with a core which contains anabsorption-impairing drug and which is surrounded by an enteric coating.In addition, there is an outer layer that surrounds the enteric coatedcore and which contains a drug that does not impair absorption. G: Drugin Core; H: Enteric or Controlled Release Film Coat; I: Drug in FilmCoat.

FIG. 5: FIG. 5 shows a bilayer tablet configuration in which anabsorption impairing drug is in coated pellets in one layer and a drugthat does not impair absorption is in the other layer. J: Drug inPellets in Layer 1; K: Drug in Layer 2.

DEFINITIONS

A. “Long acting,” shall refer a drug having a pharmacokinetic half-lifeof at least 4 hours, and preferably at least 8-14 hours and a durationof action equal to or exceeding about 6-8 hours. Examples of long actingNSAIDs are: flurbiprofen with a half-life of about 6 hours; naproxen andnaproxen sodium with half-lives of about 12 to 15 hours and about 12 to13 hours respectively; oxaprozin with a half-life of about 42 to 50hours; etodolac with a half-life of about 7 hours; indomethacin with ahalf-life of about 4 to 6 hours; ketorolac with a half-life of up toabout 8-9 hours; nabumetone with a half-life of about 22 to 30 hours;mefenamic acid with a half-life of up to about 4 hours; and piroxicamwith a half-life about of about 4 to 6 hours. If an analgesic or otherdrug does not naturally have a half life sufficient to be long-acting,it can be made long-acting by the way in which it is formulated. Unlessotherwise indicated, reference to a “long-acting” drug shall includedrugs specially formulated to be long-acting. Methods for makingappropriate long-acting formulations are well known in the art (seee.g., Remington's Pharmaceutical Sciences, 16.sup.th ed., A. Osloeditor, Easton, Pa. (1980); Controlled Drug Delivery, Edith Mathiowitz,John Wiley & Sons (1999), ISBN: 0471148288).

B. “Therapeutically effective amount” as to drug dosage shall mean adosage that provides the specific pharmacological response for which thedrug is administered in a significant number of subjects in need of suchtreatment. For drugs already on the market, a therapeutically effectiveamount shall include dosages that have been determined as safe andeffective for any indication. Nevertheless, this does not necessarilyexclude substantially lesser (or greater) dosages than establishedminimum (or maximum) dosages in particular cases.

C. “Co-timely” with respect to drug administration means administrationof a second drug while a first drug is still present in atherapeutically effective amount.

D. “Coordinated” in the practice of the present invention meansadministration of drugs in such a manner that effective plasma levels ofthe non-absorption impairing drug (or drugs) are present in a subjectbefore the absorption-impairing drug is released.

E. “Unit dosage from” shall mean a single drug administration entity. Byway of example, a single tablet, or capsule would be a unit dosage form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to oral dosage forms for theco-administration of at least two drugs, one which impairsgastrointestinal absorption and one which does not. The dosage forms aredesigned so that the drug impairing absorption is not released untilafter the non-impairing drug has been released and had an opportunity tobe at least partially absorbed.

For convenience, the rate at which the non-impairing drug is absorbed isexpressed as Tmax2, which is defined as the time interval between theingestion of the drug when administered as the sole therapeutic agent,and the time at which the plasma concentration of the drug peaks.Release of the absorption impairing drug should generally be delayed fora period equivalent to, at a minimum, one-fourth Tmax2. One preferredway to delay release is by surrounding the absorption impairing drugwith a membrane that degrades or dissolves at a preselected rate.However, other alternatives may also be used. For example, mixing inpolymers (e.g., hydroxypropylmethylcellulose) that delay drug release(e.g., by swelling) with a drug such as a triptan or opioid analgesicmay be used

Making of Pharmaceutical Preparations

The pharmaceutical compositions of the invention include tablets andcapsules that can be made in accordance with methods that are standardin the art (see, e.g., Remington's Pharmaceutical Sciences, 16^(th) ed.,A Oslo editor, Easton, Pa. (1980)). Drugs and drug combinations willtypically be prepared in admixture with conventional excipients.Suitable carriers include, but are not limited to: water; saltsolutions; alcohols; gum arabic; vegetable oils; benzyl alcohols;polyethylene glycols; gelatin; carbohydrates such as lactose, amylose orstarch; magnesium stearate; talc; silicic acid; paraffin; perfume oil;fatty acid esters; hydroxymethylcellulose; polyvinyl pyrrolidone; etc.The pharmaceutical preparations can be sterilized and, if desired, mixedwith auxiliary agents such as: lubricants, preservatives, disintegrants;stabilizers; wetting agents; emulsifiers; salts; buffers; coloringagents; flavoring agents; or aromatic substances.

Membranes that delay the release of absorption-impairing drugs may beapplied to a core or layer containing the drug using standard coatingtechniques. The coating materials may be dissolved or dispersed inorganic or aqueous solvents and may include one or more of the followingmaterials: methacrylic acid copolymers, shellac,hydroxypropyl-methcellulose phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose trimellitate, carboxymethylethyl-cellulose,cellulose acetate phthalate, ethylcellulose or other suitable coatingpolymer(s). The rate at which membranes dissolve can be controlled bythe polymer or combination of polymers selected and/or ratio of pendantgroups, and may be pH dependent. For example, dissolutioncharacteristics of the polymer film can be altered by the ratio of freecarboxyl groups to ester groups. Membranes may also containpharmaceutically acceptable plasticizers such as triethyl citrate,dibutyl phthalate, triacetin, polyethylene glycols, polysorbates orother plasticizers. Additives such as dispersants, colorants,anti-adhering and anti-foaming agents may also be included. The degreeto which a membrane delays drug release can also be controlled byaltering the thickness of the membrane. The same polymers may also bemixed with drugs to delay release.

For any given membrane composition, the timing of release can beempirically determined using in vitro experimental techniques that arewell known in the art (see e.g., procedures described in the UnitedStates Pharmacopeia, see <721> and <724>). For example, the release of amarker substance into a medium mimicking in vivo conditions may bedetermined for membranes of various thickness. In this manner, acorrelation between, for example, thickness and release can beestablished and used to in constructing a membrane that will releasedrug at a desired time.

The Making of Tablet Dosage Forms

Preferably, drug combinations will be in the form of a bi- ormulti-layer tablet. In a bilayer configuration, one portion of thetablet contains the non-absorption impairing drug (e.g., a non-narcoticanalgesic such as an NSAID) in the required dose along with appropriateexcipients, agents to aid dissolution, lubricants, fillers, etc. Thesecond portion of the tablet will contain the absorption-impairing drug(e.g., a opioid analgesic or triptan) in the required dose along withother excipients, dissolution agents, lubricants, fillers, etc. Theabsorption-impairing drug may be surrounded by a membrane which does notdissolve until at least one-fourth Tmax of the non-impairing drug.Alternatively, the release of the aborption-impairing drug can bedelayed by mixing this drug with an agent that delays its release, e.g.,a polymer that swells when it comes in contact with fluid in thegastrointestinal tract. The amount of polymer to be included may bedetermined using dissolution tests as described above.

In general, tablets will be designed so that the non-impairing drug isreleased immediately after ingestion by a patient. However, there may beinstances in which, due to instability in a patient's stomach, the drugis inside an enteric coating that does not release it until the drug hasreached a patient's intestine. In these cases the value of Tmax2 willcorrespond to the period between the drug's release and the attainmentof a peak plasma concentration, plus the period of time needed for thedrug to arrive in the patient's intestine.

Dosage Forms Containing Analgesics in Combination with Triptans orOpioid Analgesics

The two most preferred combinations for use in dosage forms arenon-narcotic analgesics (particularly NSAIDs, with long acting NSAIDsbeing preferred) together with either triptans or opioid analgesics. Inboth cases, the non-narcotic analgesic should be released first,preferably within 5 minutes after ingestion, and the release of triptanor opioid analgesic is delayed for at least 10 minutes after ingestionand preferably for at least 20, 30 or 60 minutes. The triptan/NSAIDcombinations will be useful primarily in the treatment of migraine andcombinations involving opioid analgesics will be useful in treatingother types of acute or chronic pain. Guidance concerning the amount ofthese agents to be used in tablets or capsules and the daily dosage thatshould be administered to patients is provided in Tables 1-3. All of theagents listed are well known in the art and may be either purchasedcommercially or manufactured using established methodology. The numbersprovided in the tables refer to the active component in drug compounds.However, it will be understood that any pharmaceutically acceptable formof a drug may be used. It will also be understood that the informationin the tables is for guidance only. Actual dosages and tablet amountsmay be altered by physicians and other medical personnel based uponclinical and practical considerations.

TABLE 1 Dosage Information for Opioid analgesics Maximum DailyApproximate Amount per Therapeutic Dose Drug Tablet or Capsule (mg)(mg/kg body wt/day) Alfentanil 10-200 mg 3.0 (preferably 20-100 mg)Buprenorphine 1-20 mg .015 (preferably 2-10 mg) Codeine 5-100 mg 6.0(preferably 10-50 mg) Dezocine 1-200 mg 0.167 (preferably 10-100 mg)Fentanyl 0.05-5.0 mg .0005 (preferably 0.1-2.0 mg) Dihydrocodeine 10-200mg 3.2 (preferably 20-100 mg) Hydrocodone 1-100 mg 0.75 (preferably 5-50mg) Hydromorphone 1-100 mg 0.40 (preferably 2-50 mg) Levorphanol 0.5-50mg 0.15 (preferably 1-20 mg) Meperidine 5-200 mg 15 (preferably 20-150mg) Methadone 1-100 mg 0.5 (preferably 2-50 mg) Morphine 5-200 mg 1.67(preferably 10-150 mg) Nalbuphine 1-150 mg 1.0 (preferably 5-100 mg)Oxycodone 1-200 mg 0.333 (preferably 5-100 mg) Oxymorphone 0.5-100 mg0.15 (preferably 1-50 mg) Pentazocine 1-100 mg 0.5 (preferably 2-50 mg)Propiram 10-200 mg 2.5 (preferably 20-150 mg) Propoxyphene 10-200 mg 6.5(preferably 20-100 mg) Sufentanil .001-0.1 mg .025 Tramadol 10-200 mg6.67 (preferably 20-100 mg)

TABLE 2 Dosing Information for Triptans Approximate Amount Maximum DailyDrug per Tablet or Capsule Therapeutic Dose Sumatriptan 5-200 mg 0.2mg/kg/day (preferably 20-100 mg) Eletriptan 10-100 mg approximately 80mg (preferably 20-40 mg) Rizatriptan 1-50 mg 0.5 mg/kg/day (preferably3-15 mg) Frovatriptan 1-30 mg 0.125 mg/kg/day (preferably 2-10 mg)Almotriptan 1-30 mg 25 mg (preferably 5-20 mg) Zolmitriptan 1-30 mg 10mg (preferably 2-20 mg) Naratriptan 0.1-20 mg 0.0833 mg/kg/day(preferably 0.5-10 mg)

NSAIDs compatible with the present invention are well known in the artand are either commercially available or can be synthesized usingstandard techniques of medicinal chemistry. Although the dosage of NSAIDmay be adjusted by a clinician on a case-by-case basis, generalguidelines have been established in the art for many of these compounds.

Examples of NSAIDs (with typical daily doses in parentheses) are asfollows: propionic acids (fenoprofen (1500 mg); flurbiprofen (200 mg);suprofen; benoxaprofen; ibuprofen (1600 mg); ketoprofen (200 mg);naproxen (750 mg); oxaprozin (1200 mg)); acetic acids (diclofenac (100mg); aceclofenac (200 mg); etodolac (1200 mg); indomethacin (75-150 mg);ketorolac (10-30 mg)); ketones (nabumetone (1500 mg); sulindac (300 mg);tolmetin (800 mg)); fenamates (meclofenamate (400 mg); tolfenamic acid(400 mg); mefanamic acid); oxicams (droxicam; piroxicam (20 mg);lornoxicam (30 mg); meloxicam (15 mg); tenoxicam) salicylates (aspirin;diflunisal); pyrazolinates (oxyphenbutazone; azapropazone;phenylbutazone); COX-2 inhibitors (rofecoxib (50 mg); valdecoxib (20-40mg); etorocoxib (60-120 mg); celecoxib (200 mg); lumiracoxib (100-200mg); JTE-522; NS-398; and CS-502).

While the experienced clinician is able to monitor and adjust dosagesfor each patient relative to the severity of pain and the presence ofside effects, approximate maximum daily dosages are as follows:flurbiprofen 300 mg; naproxen 1500 mg; naproxen sodium 1650 mg;oxaprozin 1800 mg; etodolac 1200 mg; indomethacin 150-200 mg; ketorolac120 mg i.m. and 40 mg when taken orally; nabumetone 2000 mg; mefenamicacid 1000 mg; and piroxicam 20 mg. In particular instances, however,exceeding these “maximum” dosages may be the therapeutic choice of amedical professional.

TABLE 3 Dosing Information for select NSAIDs Approximate Amount MaximumDaily Drug per Tablet or Capsule Therapeutic Dose Ibuprofen 20-1000 mg3200 mg (preferably 50-800 mg) Flurbiprofen 20-200 mg 300 mg (preferably50-100 mg) Ketoprofen 15-100 mg 300 mg (preferably 25-75 mg) Naproxen100-1000 mg 1500 mg (preferably 200-600 mg) Oxaprozin 200-800 mg 1800 mg(preferably 300-600 mg) Etodolac 100-600 mg 1200 mg (preferably 200-400mg) Ketorolac 1-100 mg 40 mg (preferably 5-50 mg) Nabumetone 300-1000 mg2000 mg (preferably 400-800 mg) Mefenamic Acid 50-500 mg 1000 mg(preferably 200-400 mg) Indomethacin 10-100 mg 200 mg (preferably 20-80mg) Piroxicam 5-40 mg — (preferably 10-20 mg) Celecoxib 50-400 mg 400 mg(preferably 100-200 mg) Rofecoxib 5-100 mg — (preferably 10-50 mg)

Use in Therapeutic Methods

The dosage forms described above can be used as an improvement in anyexisting therapy involving the co-administration of a drug that impairsgastrointestinal absorption together with one or more drugs that do notimpair absorption. Thus, the tablets and capsules may be used to replacedosage forms containing one component of the combination or dosage formswhich contain both components but in which the release of drugs is notcoordinated in the manner described herein. Dosages administered usingthe tablets and capsules of the present invention should beapproximately the same as those given when individual drugs of thecombination are separately administered. In the case of combinationsinvolving triptans and non-narcotic analgesics, guidance concerningdosages and the amount present in tablets or capsules may be found inTables 2 and 3 above. These dosage forms will be used primarily fortreating patients with migraine headache and may be taken at the onsetof symptoms associated with a migraine attack.

Combinations involving opioid analgesic and non-narcotic analgesics canbe used in treating a wide variety of different types of acute orchronic pain, including post-operative pain and pain associated withchronic diseases such as cancer. Guidance concerning dosages and theamount of each drug present in tablets or capsules may be found inTables 1 and 3. In all cases, sufficient drug should be administered toachieve the intended therapeutic benefit, i.e., relief of pain.

EXAMPLES Example 1 Triptan and NSAID

The present example describes a compression-coated or press-coatedtablet consisting of sumatriptan succinate in the core and naproxensodium surrounding the core. Refer to FIG. 1 for schematic of thetablet.

TABLE 4 Composition for Core (40 mg sumatriptan) Ingredient Mg/TabletIntra-Granular Ingredients Sumatriptan Succinate, USP¹ 56.0 LactoseMonohydrate, NF 56.0 Purified Water, USP² QS Extra-Granular IngredientsAnhydrous Lactose, NF 112.0 Microcrystalline Cellulose, NF 26.2Croscarmellose Sodium, NF 2.54 Magnesium Stearate, NF 1.27 Total 254.0¹56.0 mg of sumatriptan succinate is equivalent to 40 mg of sumatriptan²Purified Water, USP is removed during the drying process

TABLE 5 Composition of layer outside of core (500 mg naproxen sodium)Ingredient Mg/Tablet Intra-Granular Ingredients Naproxen Sodium, USP500.0 Microcrystalline Cellulose, NF 52.95 Povidone, USP 23.60 PurifiedWater, USP¹ Extra-Granular Ingredients Microcrystalline Cellulose, NF52.95 Croscarmellose Sodium, NF 13.50 Talc, USP 27.0 Magnesium Stearate,NF 5.0 Total 675.0 ¹Purified Water, USP is removed during the dryingprocess

The intra-granular ingredients from Table 4 (sumatriptan succinate) arecharged into high shear granulator (i.e., Gral, PMA). The ingredientsare dry mixed and a granulating solution (purified water) is then addedwhile continuously mixing. Mixing is continued until a desiredgranulation is achieved. The wet granules are removed from the highshear granulator and are dried in a fluid bed dryer (i.e., Glatt) toachieve a moisture of <1%. The dried granulation is milled using asuitable mill (i.e., Quadro Comil, Fitzmill). The milled granulation andextra-granular ingredients from Table 4 are then added to a blender(e.g., V-Blender, tote blender) and blended until uniform. Magnesiumstearate is then added and blended. The blend is discharged intocontainers (e.g., drums).

Similarly, the intra-granular ingredients from Table 5 (naproxen sodium)are charged into a high shear granulator (e.g., Gral, PMA) and drymixed. Granulating solution (purified water) is then added whilecontinuously mixing to a desired granulation. The wet granules areremoved from the high shear granulator and dried in a fluid bed dryer toachieve a moisture of 1-5%. The dried granulation is milled using asuitable mill (e.g., Quadro Comil, Fitzmill). The milled granulation andextra-granular ingredients from Table 5 are then added to a blender(e.g., V-Blender, tote blender) and blended until uniform. Lubricants,magnesium stearate and talc, are then added and blended. The blend isdischarged into suitable containers (e.g., drums).

Tablets are compressed using a compression-coated tablet press (e.g.,Manesty Drycota) with the blend of ingredients in Table 4 as the core orinner layer and ingredients in Table 5 outside the core in an outerlayer. The tablets can be film coated in a coating pan (e.g., AccelaCota) for aesthetic purposes.

Example 2 Opioid Analgesic and NSAID

This example describes a bilayer tablet consisting of sustained releasehydrocodone and naproxen sodium. Refer to FIG. 2 for a schematic of thetablet or FIG. 5 for tablet containing pellets.

TABLE 6 Composition for Layer One (10 mg hydrocodone bitartrate)Ingredient Mg/Tablet Intra-Granular Ingredients Hydrocodone Bitartrate,USP 10.0 Microcrystalline Cellulose, NF 37.5 Povidone, USP 15.0Hydroxypropyl methylcellulose (Methocel K4M) 45.0 Purified Water, USP¹QS Extra-Granular Ingredients Microcrystalline Cellulose, NF 45.0Magnesium Stearate, NF 1.5 Total 154.0 ¹Purified Water, USP is removedduring the drying process

TABLE 7 Composition for Layer 2 (400 mg naproxen sodium) IngredientMg/Tablet Intra-Granular Ingredients Naproxen Sodium, USP 400.0Microcrystalline Cellulose, NF 42.2 Povidone, USP 18.9 Purified Water,USP¹ QS Extra-Granular Ingredients Microcrystalline Cellulose, NF 42.2Croscarmellose Sodium, NF 10.8 Talc, USP 21.6 Magnesium Stearate, NF 4.0Total 540.0 ¹Purified Water, USP is removed during the drying process

The intra-granular ingredients from Table 6 (hydrocodone bitartrate) arecharged into a high shear granulator (e.g., Gral, PMA) and dry mixed.Granulating solution (purified water) is then added while continuouslymixing. Mixing is continued until a suitable granulation is achieved.The wet granules are then removed from the high shear granulator anddried in a fluid bed dryer (e.g., Glatt) to achieve a moisture of 1-5%.The dried granulation is milled using a mill (e.g., Quadro Comil,Fitzmill). The milled granulation and extra-granular ingredients fromTable 6 are then added to a blender (e.g., V-Blender, tote blender) andblended until uniform. Magnesium stearate is then added and blended. Theblend is discharged into suitable containers (e.g., drums).Alternatively, pellets are produced using a rotary processor for theprocesses of extrusion, spheronization and drying. The intra-granularingredients listed in Table 6 including hydrocodone bitartrate,microcrystalline cellulose, povidone and purified water are formed intopellets. These pellets are then film coated with Surelease which is anaqueous dispersion of ethylcellulose and plasticizers. The pellets andthe extra-granular ingredients from Table 6 are then added to a blenderand blended until uniform.

Similarly, the intra-granular ingredients from Table 7 (naproxen sodium)are charged into a high shear granulator (e.g., Gral, PMA) and drymixed. Granulating solution (purified water) is then added whilecontinuously mixing. Mixing is continued until a suitable granulation isachieved. The wet granules are removed from the high shear granulatorand dried in a fluid bed dryer to achieve a moisture of 1-5%. The driedgranulation is milled using a suitable mill (e.g., Quadro Comil,Fitzmill). The milled granulation and extra-granular ingredients fromTable 7 are then added to a blender (e.g., V-Blender, tote blender) andblended until uniform. Lubricants, magnesium stearate and talc, are thenadded and blended. The blend is discharged into suitable containers(e.g., drums).

Tablets are compressed into bilayer tablets using a multi-layered tabletpress (e.g., Courtoy, Stokes) with blend (or blend containing pellets)from ingredients in Table 6 and ingredients in Table 7. A barrier layer,consisting of an 80:20 mixture of anhydrous lactose, NF andmicrocrystalline cellulose, NF may be included between the hydrocodonebitartrate and naproxen sodium layers so that a trilayer tablet iscompressed. The tablets may be film coated for aesthetic purposes.

Example 3 Opioid Analgesic and NSAID

The present example describes a hydrocodone core tablet with lornoxicamin a filmcoat. Refer to FIG. 3 for a schematic of the tablet.

TABLE 8 Composition for core tablet (10 mg hydrocodone bitartrate)Ingredient Mg/Tablet Intra-Granular Ingredients Hydrocodone Bitartrate,USP 10.0 Microcrystalline Cellulose, NF 35.0 Anhydrous Lactose, NF 103.0Povidone, USP 8.0 Purified Water, USP¹ QS Extra-Granular IngredientsMicrocrystalline Cellulose, NF 35.0 Croscarmellose Sodium, NF 8.0Magnesium Stearate, NF 1.0 Total 200 ¹Purified Water, USP is removedduring the drying process

TABLE 9 Composition of film coat containing lornoxicam IngredientMg/Tablet Active Film Coat Opadry Clear 30.0 Piroxicam 20.0 Polysorbate80, NF 2.0 Sodium Phosphate Dibasic Anhydrous, USP 1.0 Purified Water,USP¹ QS Color Film Coat Opadry White 10.0 Purified Water, USP¹ QS¹Purified Water, USP is removed during the film coating process.

The intragranular ingredients from Table 8 (hydrocodone bitartrate) arecharged into a high shear granulator (e.g., Gral, PMA) and dry mixed.Granulating solution (purified water) is then added while continuouslymixing. Mixing is continued until the desired granulation is achieved.The wet granules are removed from the high shear granulator and dried ina fluid bed dryer (e.g., Glatt) to achieve a moisture of 1-5%. The driedgranulation is milled using a suitable mill (e.g., Quadro Comil,Fitzmill). The milled granulation and extra-granular ingredients fromTable 8 are then added to a blender (e.g., V-Blender, tote blender) andblended until uniform. Magnesium stearate is then added and blended. Theblend is discharged into suitable containers (e.g., drums). Tablets arecompressed from the blend on a tablet press.

The active coating suspension (Table 9) is prepared by mixingpolysorbate 80, sodium phosphate buffer, and lornoxicam. Purified wateris added and mixed. Opadry Clear is added to the suspension and mixed.The core tablets are loaded into a coating pan and the active coatingsuspension is applied to the core tablets. Alternatively, the coretablets may be film coated with a subcoat consisting of Opadry Clearprior to the active film coat. Another alternative is that the coretablets may be film coated with a layer consisting of Surelease which isan aqueous dispersion consisting of ethylcellulose and plasticizers. Awhite coating suspension is prepared by combining Opadry White andpurified water and mixing until dispersed. The white coating suspensionis then applied to the tablets.

Example 4 Opioid Analgesic and NSAID

Example 4 is a delayed release hydrocodone tablet with lornoxicam infilm coat. Refer to FIG. 4 for a schematic of the tablet.

TABLE 10 Enteric Film Coat Ingredient Mg/Tablet Methacrylic AcidCopolymer Dispersion, NF 24.9 (Eudragit L30D-55) Triethyl Citrate, NF3.7 Glyceryl Monostearate, NF 1.0 Polysorbate 80, NF 0.4 Purified Water,USP¹ QS ¹Purified Water, USP is removed during the film coating process

The core tablet described in Example 3 is film coated with an entericfilm coat. The ingredients for the enteric coat are listed in Table 10.Glyceryl monostearate is melted in purified water at approx. 60° C.Polysorbate 80 is added and the mixture is cooled to room temperature.Triethyl citrate is added to the methacrylic acid copolymer dispersionand mixed. The glyceryl monostearate dispersion is added to themethacrylic acid copolymer dispersion and mixed until uniform. Theresultant dispersion is applied to the core tablets in a coating pan.The active film coat and white color coat described in Table 9 are thenapplied to the tablets.

Example 5 Opioid Analgesic and NSAID

Example 5 is a controlled release hydrocodone tablet with lornoxicam infilm coat. Refer to FIG. 4 for a schematic of the tablet.

TABLE 11 Controlled Release Film Coat Ingredient Mg/Tablet Surelease20.0 Purified Water, USP¹ QS ¹Purified Water, USP is removed during thefilm coating process

The core tablet described in Example 3 is film coated with a film coatcontaining Surelease as shown in Table 11. Surelease is supplied byColorcon as a 25% w/w aqueous dispersion containing ethylcellulose andplasticizers. Surelease is mixed with additional purified water asappropriate and the resultant dispersion is applied to the core tabletsin a coating pan. The active film coat and white color coat described inTable 9 are then applied to the tablets.

Example 6 Triptan and NSAID Using Bicarbonate in the NSAID Layer toSpeed Absorption

The present example describes a compression-coated or press-coatedtablet consisting of sumatriptan succinate in the core and naproxensodium surrounding the core. Refer to FIG. 1 for schematic of thetablet.

TABLE 12 Composition for Core (40 mg sumatriptan) Ingredient Mg/TabletIntra-Granular Ingredients Sumatriptan Succinate, USP¹ 56.0 LactoseMonohydrate, NF 56.0 Purified Water, USP² QS Extra-Granular IngredientsAnhydrous Lactose, NF 112.0 Microcrystalline Cellulose, NF 26.2Croscarmellose Sodium, NF 2.54 Magnesium Stearate, NF 1.27 Total 254.0¹56.0 mg of sumatriptan succinate is equivalent to 40 mg of sumatriptan²Purified Water, USP is removed during the drying process

TABLE 13 Composition of layer outside of core (500 mg naproxen sodium)Ingredient Mg/Tablet Intra-Granular Ingredients Naproxen Sodium, USP500.0 Microcrystalline Cellulose, NF 64.0 Povidone, USP 28.0 PurifiedWater, USP¹ Extra-Granular Ingredients Sodium Bicarbonate, USP 90.0Microcrystalline Cellulose, NF 64.0 Croscarmellose Sodium, NF 16.0 Talc,USP 32.0 Magnesium Stearate, NF 6.0 Total 800.0 ¹Purified Water, USP isremoved during the drying process

The intra-granular ingredients from Table 12 (sumatriptan succinate) arecharged into high shear granulator (i.e., Gral, PMA). The ingredientsare dry mixed and a granulating solution (purified water) is then addedwhile continuously mixing. Mixing is continued until a desiredgranulation is achieved. The wet granules are removed from the highshear granulator and are dried in a fluid bed dryer (i.e., Glatt) toachieve a moisture of <1%. The dried granulation is milled using asuitable mill (i.e., Quadro Comil, Fitzmill). The milled granulation andextra-granular ingredients from Table 12 are then added to a blender(e.g., V-Blender, tote blender) and blended until uniform. Magnesiumstearate is then added and blended. The blend is discharged intocontainers (e.g., drums).

Similarly, the intra-granular ingredients from Table 13 (naproxensodium) are charged into a high shear granulator (e.g., Gral, PMA) anddry mixed. Granulating solution (purified water) is then added whilecontinuously mixing to a desired granulation. The wet granules areremoved from the high shear granulator and dried in a fluid bed dryer toachieve a moisture of 1-5%. The dried granulation is milled using asuitable mill (e.g., Quadro Comil, Fitzmill). The milled granulation andextra-granular ingredients from Table 13 are then added to a blender(e.g., V-Blender, tote blender) and blended until uniform. Lubricants,magensium stearate and talc, are then added and blended. The blend isdischarged into suitable containers (e.g., drums).

Tablets are compressed using a compression-coated tablet press (e.g.,Manesty Drycota) with the blend of ingredients in Table 12 as the coreor inner layer and ingredients in Table 13 outside the core in an outerlayer. The tablets can be film coated in a coating pan (e.g., AccelaCota) for aesthetic purposes.

Example 7 Opioid Analgesic and NSAID Using Bicarbonate in the NSAIDLayer to Speed Absorption

This example describes a bilayer tablet consisting of sustained releasehydrocodone and naproxen sodium. Refer to FIG. 2 for a schematic of thetablet or FIG. 5 for tablet containing pellets.

TABLE 14 Composition for Layer One (10 mg hydrocodone bitartrate)Ingredient Mg/Tablet Intra-Granular Ingredients Hydrocodone Bitartrate,USP 10.0 Microcrystalline Cellulose, NF 37.5 Povidone, USP 15.0Hydroxypropyl methylcellulose (Methocel K4M) 45.0 Purified Water, USP¹QS Extra-Granular Ingredients Microcrystalline Cellulose, NF 45.0Magnesium Stearate, NF 1.5 Total 154.0 ¹Purified Water, USP is removedduring the drying process

TABLE 15 Composition for Layer 2 (400 mg naproxen sodium) IngredientMg/Tablet Intra-Granular Ingredients Naproxen Sodium, USP 400.0Microcrystalline Cellulose, NF 52.3 Povidone, USP 23.6 Purified Water,USP¹ QS Extra-Granular Ingredients Sodium Bicarbonate, USP 101.3Microcrystalline Cellulose, NF 52.3 Croscarmellose Sodium, NF 13.5 Talc,USP 27.0 Magnesium Stearate, NF 5.0 Total 675.0 ¹Purified Water, USP isremoved during the drying process

The intra-granular ingredients from Table 14 (hydrocodone bitartrate)are charged into a high shear granulator (e.g., Gral, PMA) and drymixed. Granulating solution (purified water) is then added whilecontinuously mixing. Mixing is continued until a suitable granulation isachieved. The wet granules are then removed from the high sheargranulator and dried in a fluid bed dryer (e.g., Glatt) to achieve amoisture of 1-5%. The dried granulation is milled using a mill (e.g.,Quadro Comil, Fitzmill). The milled granulation and extra-granularingredients from Table 14 are then added to a blender (e.g., V-Blender,tote blender) and blended until uniform. Magnesium stearate is thenadded and blended. The blend is discharged into suitable containers(e.g., drums). Alternatively, pellets are produced using a rotaryprocessor for the processes of extrusion, spheronization and drying. Theintra-granular ingredients listed in Table 14 including hydrocodonebitartrate, microcrystalline cellulose, povidone and purified water areformed into pellets. These pelletes are then film coated with Sureleasewhich is an aqueous dispersion of ethylcellulose and plasticizers. Thepellets and the extra-granular ingredients from Table 14 are then addedto a blender and blended until uniform.

Similarly, the intra-granular ingredients from Table 15 (naproxensodium) are charged into a high shear granulator (e.g., Gral, PMA) anddry mixed. Granulating solution (purified water) is then added whilecontinuously mixing. Mixing is continued until a suitable granulation isachieved. The wet granules are removed from the high shear granulatorand dried in a fluid bed dryer to achieve a moisture of 1-5%. The driedgranulation is milled using a suitable mill (e.g., Quadro Comil,Fitzmill). The milled granulation and extra-granular ingredients fromTable 15 are then added to a blender (e.g., V-Blender, tote blender) andblended until uniform. Lubricants, magnesium stearate and talc, are thenadded and blended. The blend is discharged into suitable containers(e.g., drums).

Tablets are compressed into bilayer tablets using a multi-layered tabletpress (e.g., Courtoy, Stokes) with blend (or blend containing pellets)from ingredients in Table 14 and ingredients in Table 15. A barrierlayer, consisting of an 80:20 mixture of anhydrous lactose, NF andmicrocrystalline cellulose, NF may be included between the hydrocodonebitartrate and naproxen sodium layers so that a trilayer tablet iscompressed. The tablets may be film coated for aesthetic purposes.

All references cited herein are fully incorporated by reference. Havingnow fully described the invention, it will be understood by those ofskill in the art that the invention may be practiced within a wide andequivalent range of conditions, parameters and the like, withoutaffecting the spirit or scope of the invention or any embodimentthereof.

What is claimed is:
 1. A pharmaceutical composition in unit dosage formfor oral administration, comprising: a) a therapeutically effectiveamount of a first drug, wherein said first drug impairs the absorptionof medication from the gastrointestinal tract of patients andessentially all of said first drug is either surrounded by a membranethat delays its release after ingestion or is formulated with componentsthat delay its release after ingestion; and b) a therapeuticallyeffective amount of a second drug, wherein said second drug does notimpair the absorption of medication from the gastrointestinal tract ofpatients; and wherein, upon ingestion of said unit dosage form by apatient, i) said second drug is released from said unit dosage form intothe gastrointestinal tract of said patient before said first drug; andii said first drug is not released from said unit dosage form for aperiod of time equal to at least one-fourth Tmax2, wherein Tmax2 is thetime needed for said second drug to reach peak plasma concentration whensaid second drug is administered to a patient as the sole active agent.2. The pharmaceutical composition of claim 1, wherein said unit dosageform is a multilayer tablet.
 3. The pharmaceutical composition of claim2, wherein the release of said first drug is delayed for a minimum of 15minutes after ingestion and said second drug is released from saiddosage from within 5 minutes after ingestion.
 4. The pharmaceuticalcomposition of claim 3, wherein: a) essentially all of said first drugis in a single core layer; and b) essentially all of said second drug islocated in one or more layers outside of said core layer that include adisintegrant or a compound that causes effervescence.
 5. Thepharmaceutical composition of claim 1, wherein said dosage form is acapsule.
 6. The pharmaceutical composition of claim 5, wherein therelease of said first drug is delayed for a minimum of 15 minutes afteringestion and said second drug is released from said dosage from within5 minutes after ingestion.
 7. The pharmaceutical composition of claim 6,wherein: a) said capsule comprises multiple particles of said firstdrug; and b) essentially all of said second drug is located outside ofsaid particles together with a disintegrant or a compound that causeseffervescence.
 8. The pharmaceutical composition of claim 1, whereinsaid first drug is a triptan.
 9. The pharmaceutical composition of claim8, wherein said triptan is selected from the group consisting of:sumatriptan, eletriptan, rizatriptan, frovatriptan, almotriptan,zolmitriptan and naratriptan.
 10. The pharmaceutical composition ofclaim 9, wherein said triptan is sumatriptan present in said unit dosageform in an amount of between 25 and 100 mg and said second drug iseither acetaminophen or an NSAID selected from the group consisting of:ibuprofen; flurbiprofen; ketoprofen; oxaprozin; etodolac; ketorolac;nabumetone; mefenamic acid; indomethacin; piroxicam; celecoxib; androfecoxib.
 11. A pharmaceutical composition in unit dosage form for oraladministration, comprising: a) a first drug, wherein said first drug isa therapeutically effective amount of a triptan; and b) atherapeutically effective amount of a non-narcotic analgesic selectedfrom the group consisting of: acetaminophen and an NSAID; and wherein,i) said non-narcotic analgesic is released from said unit dosage forminto the gastrointestinal tract of said patient within 5 minutes aftersaid dosage form is ingested; and ii) said triptan or opioid analgesicis either surrounded by a membrane that does not release it from saidunit dosage form for at least 20 minutes after said dosage form isingested or said triptan is formulated with components that delay itsrelease for at least 20 minutes after said dosage form is ingested. 12.The pharmaceutical composition of claim 11, wherein said first drug is atriptan selected from the group consisting of: sumatriptan, eletriptan,rizatriptan, frovatriptan, almotriptan, zolmitriptan and naratriptan.13. The pharmaceutical composition of claim 12, wherein saidnon-narcotic analgesic is an NSAID selected from the group consistingof: naproxen; ibuprofen; flurbiprofen; ketoprofen; oxaprozin; etodolac;ketorolac; nabumetone; mefenamic acid; indomethacin; piroxicam;celecoxib; and rofecoxib.
 14. The pharmaceutical composition of claim13, wherein said trip tan is sumatriptan present in said unit dosageform in an amount of between 25 and 100 mg and said non-narcoticanalgesic is naproxen, present in said unit dosage form in an amount ofbetween 200 and 600 mg.
 15. A method of treating a patient for paincomprising administering to said patient a therapeutically effectiveamount of the pharmaceutical composition of claim 1.